An Immune-Based Therapeutic Approach for Prostate Cancer. Since the immune system has the capacity to recognize and destroy tumor cells, significant efforts have been devoted to the development of therapeutic vaccines for cancer. Both cytotoxic T lymphocytes (CTL) and T helper (Th) lymphocytes can react with antigens expressed by tumor cells and produce protective and therapeutic effects. CTL and Th cells recognize antigens in the form of peptides that form complexes with products of the major histocompatibility complex (MHC). Peptide-based vaccines that have been so far tested in the clinic (mostly in patients with malignant melanoma) have shown to be suboptimal in generating potent immune responses and the desired anti-tumor effects. Thus, it is clear that additional strategies to manipulate the immune system will be required to produce effective anti-tumor vaccines. Some of strategies include the use of novel and potent adjuvants, the disruption of lymphocyte homeostasis and by blocking immune suppressive activities that are present in cancer patients. Our previous work has resulted in the identification of several peptides derived from two prostate-associated proteins (PSMA and TARP) that are recognized by prostate tumor reactive CTL and Th lymphocytes. Additional work in a mouse model system resulted in the development of a topical (transcutaneous) vaccination technique that elicits effective anti-tumor immune responses. We now propose to translate these findings into the clinical setting. Here, we propose to carry out a clinical study to assess the safety and immunogenicity of a topical peptide vaccine formulated with a strong adjuvant in prostate cancer patients (aim 1). Because our recent preclinical studies have shown that vaccination of recently castrated animals enhances immune responses, we will include in this clinical study, patients that concurrently undergoing androgen ablation therapy. Being aware that immune responses in cancer patients, specially those in advanced stages may be compromised by the presence of tumor-derived suppressor factors, we propose to study therapeutic strategies that may help overcome some of these barriers. Thus, we will use animal tumor model systems to explore novel approaches to block various immune suppressive activities that are known to inhibit immune responses in the cancer setting (aim 2). The completion of these aims will result the development of novel and effective T-cell based immune therapy for the treatment of prostate cancer.